In 1968, the world has been infected with a plague that turns humans into vampiric creatures that cannot stand sunlight, fear mirrors, and are repelled by garlic. Doctor Robert Morgan (Vincent Price) spends the day hunting for vampires, killing them, and burning their bodies. At night, he locks himself inside his house. In a flashback, we see that his wife Virginia and daughter Kathy died of the plague before it was widely known that the dead would return to life. Instead of bringing his wife to the public burning pit, he secretly buried her, and she returned to his home as a zombie and attacked him. He believes he is immune to the bacteria from an infected bat-bite when he was stationed in Panama, and that is why he is still alive.
One day a wounded dog appears on his doorstep. He takes it in and treats its wounds, but it is too infected, and he has to kill it with a wooden stake. He becomes even more depressed and lonely. He sees a woman named Ruth Collins (Franca Bettoia) in the distance. At first she runs from him, but he convinces her to come home with him. He discovers that she is infected when she tries to inject herself with a vaccine. She is part of a group, infected but under treatment, that are keeping an eye on him. They are hoping to rebuild society and believe that many of the vampires he destroyed were still alive. While she sleeps, he transfuses his own blood into her and cures her, but her people attack. He flees but they pursue. He uses guns and tear-gas grenades stolen from a police station. He is struck with a spear. He renounces her people as freaks and declares that he is the last true man on Earth as he dies.
The film was produced by Robert L. Lippert and directed by Ubaldo Ragona and Sidnet Salkow, based on the 1954 novel I Am Legend by Richard Matheson, who wrote part of the screenplay but became dissatisfied and chose to be credited as Logan Swanson, largely because the film was not directed by Fritz Lang as he had hoped. Originally, Anthony Hinds was to produce it for Hammer Films with the script by Matheson, but British censors would not allow it, so the script was resold. Matheson thought the finished film was a faithful adaptation of his book but called it inept. It was shot in Italy with a mostly Italian cast and crew. It was not considered a success but became a classic later on. Vincent Price lifted real actors into his car to show what a struggle his life was but dumped only dummies into the burning pit. In the movie, the vampires were fast and agile. Later, of course, the film was remade twice with Charlton Heston and Will Smith.